TNFAIP3‐interacting protein 1 (ABIN‐1) negatively regulates caspase‐8/FADD‐dependent pyroptosis

TNFAIP3‐interacting protein 1 (TNIP1; also known as ABIN‐1) is a ubiquitin‐binding protein that suppresses death‐receptor‐ or Toll‐like receptor‐mediated apoptosis and necroptosis; however, it remains unclear whether ABIN‐1 is capable of regulating pyroptosis. In the present study, we found that, in mouse embryonic fibroblasts and macrophages, ABIN‐1 deficiency sensitized cells to poly(I:C) + TAK1 inhibitor 5Z‐7‐oxozeaenol‐induced pyroptosis besides apoptosis and necroptosis. The sensitizing effect of ABIN‐1 deficiency on pyroptosis depended on caspase‐8 and its adaptor molecule FAS‐associated death domain protein. In a mouse model of polymicrobial sepsis, myeloid‐specific deletion of Abin‐1 rendered mice more sensitive to pyroptosis, apoptosis and necroptosis, and exacerbated disease severity. Interestingly, ABIN‐1 deficiency triggered gasdermin‐E‐mediated pyroptosis in mouse embryonic fibroblasts, but induced gasdermin‐D‐mediated pyroptosis in macrophages, both in a caspase‐8‐dependent manner. Furthermore, we demonstrated that, upon poly(I:C) + 5Z‐7‐oxozeaenol stimulation, ABIN‐1 deficiency facilitates FAS‐associated death domain protein recruitment to caspase‐8; thus, the mechanism by which ABIN‐1 downregulates caspase‐8 activity is conserved in tumor necrosis factor receptor type 1 and Toll‐like receptor 3 signaling‐induced cell death. Together, our work identifies a previously unrecognized role for ABIN‐1 as a negative regulator of pyroptosis in addition to apoptosis and necroptosis, suggesting that ABIN‐1 represents a promising molecule to halt or reverse progression of refractory inflammatory disorders whose pathogenesis involves multiple forms of programmed cell death.